Although our knowledge about the formation of oligodendrocytes and their progenitors has grown enormously during the past two decades, the formulation of specific therapies to promote remyelination in patients with myelin diseases such as multiple sclerosis (MS) is still far from realization. An ideal therapy would include the use of small molecules to specifically activate the production of oligodendrocyte progenitors and remyelinating oligodendrocytes during a period of time sufficiently long to allow myelin repair. This therapy should then be controllable (i.e. therapists should be able to turn on/off the production of remyelinating oligodendrocytes to promote the right level of neural repair). With this conceptual vision of therapies for remyelination in mind, the goal of this pilot application i to obtain proof-of-concept that a set of microRNA can be used to improve remyelination in a mouse model of MS. MicroRNA (miR) are small RNA molecules which exert profound regulatory control of gene expression at the post-transcriptional level. miR-138, -219 and -338 and also members of the miR cluster 17-92 appear to positively control oligodendrocyte differentiation. Preliminary data for this application show that some of these microRNA are downregulated in the Theiler's murine encephalomyelitis virus (TMEV) model of MS. This application will challenge the hypothesis that reverting the deficiency of pro-oligodendrocyte miR in TMEV-infected mice by exogenous administration of synthetic miR (complementation therapy) will improve remyelination by increasing numbers of functional myelinating oligodendrocytes. The project is significant because it is expected to advance the understanding of how miR regulate remyelination in vivo, particularly in a model of MS. Ultimately, such understanding has the potential to contribute to improve existing immunomodulatory therapies for MS.